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中华实验和临床感染病杂志(电子版) ›› 2019, Vol. 13 ›› Issue (01) : 12 -18. doi: 10.3877/cma.j.issn.1674-1358.2019.01.003

所属专题： 专题评论； 文献；

论著

替诺福韦酯阻断乙型肝炎病毒母婴传播不同停药时间的安全性评价
彭凌1, 杨柳青2, 彭婷婷1, 彭静涵2, 袁静2, 陈凤2, 马拯华2, 刘映霞2,†()   
  1. 1. 518112　深圳市，感染病国家重点学科，深圳市第三人民医院感染科；518112　深圳市，南华大学深圳市第三人民医院感染科
    2. 518112　深圳市，感染病国家重点学科，深圳市第三人民医院感染科
  • 收稿日期:2018-05-28 出版日期:2019-02-15
  • 通信作者: 刘映霞
  • 基金资助:
    "十三五"艾滋病和病毒性肝炎等重大传染病防治科技重大专项课题(No. 2017ZX10201201); 国家自然科学基金(No. 2015，Grant81570552); 深圳市卫计委临床研究项目(No. SZLY2017014)

Safety of withdrawal during treatment with tenofovir disoproxil of mothers and infants at various time-points

Ling Peng1, Liuqing Yang2, Tingting Peng1, Jinghan Peng2, Jing Yuan2, Feng Chen2, Zhenghua Ma2, Yingxia Liu2,†()   

  1. 1. State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People’s Hospital, Shenzhen 518112, China; Department of Infectious Diseases, University of South China Shenzhen Third People’s Hospital, Shenzhen 518112, China
    2. State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People’s Hospital, Shenzhen 518112, China
  • Received:2018-05-28 Published:2019-02-15
  • Corresponding author: Yingxia Liu
  • About author:
    Corresponding author: Liu Yingxia, Email:
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引用本文：

彭凌, 杨柳青, 彭婷婷, 彭静涵, 袁静, 陈凤, 马拯华, 刘映霞. 替诺福韦酯阻断乙型肝炎病毒母婴传播不同停药时间的安全性评价[J]. 中华实验和临床感染病杂志(电子版), 2019, 13(01): 12-18.

Ling Peng, Liuqing Yang, Tingting Peng, Jinghan Peng, Jing Yuan, Feng Chen, Zhenghua Ma, Yingxia Liu. Safety of withdrawal during treatment with tenofovir disoproxil of mothers and infants at various time-points[J]. Chinese Journal of Experimental and Clinical Infectious Diseases(Electronic Edition), 2019, 13(01): 12-18.

目的

探讨采用替诺福韦酯（TDF）阻断乙型肝炎病毒（HBV）母婴传播的高HBV DNA载量孕妇分娩后不同停药时间对母婴安全性的影响。

方法

招募2015年1月至2017月12月于深圳市第三人民医院就诊的免疫耐受期HBsAg阳性孕妇109例，均于孕24～28周开始服用TDF治疗，根据简单随机化方法将入组患者分为分娩时停药组（58例）和分娩后4～12周停药组（51例）。定量检测两组孕妇抗病毒治疗后4周、8周、12周、停药时与停药后4周、8周、12周、24周的HBV DNA载量和ALT水平，并定量检测新生儿产后4周HBsAg和HBsAb水平。

结果

所有孕妇分娩前HBV DNA载量均显著降低，较基线水平差异有统计学意义（分娩时停药组：Z = 8.459、P < 0.001；分娩后4～12周停药组：Z = 7.760、P < 0.001）。停药时两组产妇HBV DNA载量差异有统计学意义（Z = 2.242、P = 0.025）。停药后4周两组产妇HBV DNA载量差异无统计学意义（Z = 1.041、P = 0.298），且较基线水平差异均无统计学意义（分娩时停药组：Z = 0.155、P = 0.877；分娩后4～12周停药组：Z = 0.376、P = 0.707）。随访至停药后24周，两组产妇产后ALT升高的发生率差异无统计学意义（χ2 = 1.319、P = 0.251），两组产妇ALT升高的中位时间点均在停药后4周，差异无统计学意义（Z = 0.196、P = 0.844）。孕期ALT升高可能引起分娩停药后ALT升高，但并非独立危险因素。20例新生儿在产后4周行外周血HBsAg、HBsAb定量检测，HBsAg均为阴性，均产生保护性抗体。

结论

妊娠中晚期使用替诺福韦酯能有效阻断HBV母婴传播；随访24周发现分娩后停药与延后停药对产后安全性的无显著影响，新生儿4周龄即能产生保护性抗体并有效发挥作用，母乳喂养是安全的。

关键词: 替诺福韦酯, 肝炎，乙型，慢性, 母婴传播, 停药, 安全性
Objective

To investigate the safety of different withdraw timepoint of tenofovir disoproxil (TDF) for pregnant women with high hepatitis B virus (HBV) DNA load in blocking mother-to-child transmission of HBV.

Methods

From January 2015 to December 2017, a total of 109 pregnant women with HBsAg positive and immunoresistance were recruited from Shenzhen Third People’s Hospital, all patients were treated with TDF at 24-28 weeks of gestation, who were divided into two groups according to simple randomized grouping method: withdrawal immediately after delivery group (58 cases) and withdrawal 4-12 weeks after delivery group (51 cases). The levels of HBV DNA and ALT were measured quantitatively at 4 weeks, 8 weeks, 12 weeks after antiviral therapy, at withdrawal and 4 weeks, 8 weeks, 12 weeks and 24 weeks after TDF discontinuation in both groups. Quantitative HBsAg and HBsAb levels of newborns at 4 weeks after birth were detected.

Results

HBV DNA levels of all pregnant women before delivery were significantly lower than those of the baseline (withdrawal immediately after delivery group: Z = 8.459, P < 0.001; withdrawal 4-12 weeks after delivery group: Z = 7.760, P < 0.001). HBV DNA levels at the timepoint of withdrawal between the two groups were significantly different (Z = 2.242, P = 0.025). The difference of HBV DNA level 4 weeks after withdrawal between the two groups was not significant (Z = 1.041, P = 0.298), and no significant differences were found compared with the baseline levels (withdrawal immediately after delivery group: Z = 0.155, P = 0.877; withdrawal at 4-12 weeks after delivery group: Z = 0.376, P = 0.707). The difference of postpartum ALT levels between the two groups following up until 24 weeks after withdrawal was not significantly different (χ2 = 1.319, P = 0.251). The median timepoint of ALT elevation of both groups was 4 weeks after withdrawal, with no significant difference (Z = 0.196, P = 0.844). The level of ALT increase during pregnancy may cause ALT increase after delivery, but it is not an independent risk factor. Total of 20 newborns were quantitatively detected for peripheral blood HBsAg and HBsAb at 4 weeks postpartum, all of them were HBsAg negative and successfully produced protective antibody.

Conclusions

TDF application in middle and late pregnancy could effectively block HBV transmission from mother to child. Following up for 24 weeks showed that there was no difference in postpartum safety between postpartum withdrawal and delayed withdrawal. Newborns produce protective antibody 4 weeks after birth and breast feeding was safe.

Key words: Tenofovir disoproxil, Hepatitis B virus, Mother-to-child transmission, Withdrawal, Safety
表1 两组孕妇基线临床资料
组别 例数 年龄（岁，±s） 乙型肝炎家族史[例（%）] 分娩史[例（%）] HBsAg（log10IU/ml）a
分娩时停药组 50 28.57 ± 3.41 22（44.00） 17（34.00） 4.54（4.36～4.68）
分娩后4～12周停药组 41 28.72 ± 4.08 18（43.90） 14（34.14） 4.48（3.72～4.61）
统计量 ? t = －0.075 χ2= 0.000 χ2 = 0.000 Z =－1.334
P值 ? 0.941 0.993 0.988 0.182
组别 例数 HBeAg（S/CO）a HBV DNA（log10IU/ml）a 基线ALT（U/L）a
分娩时停药组 50 1 389.92（1 181.37～1 541.41） 8.09（7.55～8.23） 22.50（15.00～32.00）
分娩后4～12周停药组 41 1 406.84（1 221.23～1 536.65） 7.87（7.54～8.23） 21.00（12.00～35.00）
统计量 ? Z=－0.180 Z=－0.890 Z=－0.184
P值 ? 0.857 0.373 0.854
图1 两组孕产妇HBV DNA载量变化
表2 两组产妇停药后ALT水平升高特点
组别 例数 产后4周ALT水平升高[例（%）] 停药后24周ALT水平升高[例（%）] ALT水平升高出现时间[周，M（25%～75% IQR）]
分娩时停药组 50 13（26.00） 22（44.00） 4.00（4.00～8.00）
分娩后4～12周停药组 41 5（12.20） 23（56.10） 4.00（4.00～8.00）
统计量 ? χ2= 2.067 χ2= 1.319 Z = 0.196
P值 ? 0.151 0.251 0.844
组别 例数 ALT水平最高值[U/L，M（25%～75% IQR）] 停药后24周ALT水平升高程度[例（%）]
轻度 中度
分娩时停药组 50 74.50（59.00～103.50） 11（50.00） 11（50.00）
分娩后4～12周停药组 41 69.00（60.00～98.00） 13（56.52） 10（43.48）
统计量 ? Z = 0.068 χ2= 0.192
P值 ? 0.946 0.661
表3 停药后ALT水平正常组与ALT水平升高组孕妇的临床资料
临床资料 ALT水平正常组（46例） ALT水平升高组（45例） 统计量 P值
年龄（±s，岁） 29.23 ± 3.95 28.00 ± 3.34 t = 1.613 0.110
乙型肝炎家族史[例（%）] 17（37.00） 23（51.11） χ2= 1.850 0.174
分娩史[例（%）] 14（30.43） 17（37.78） χ2= 0.546 0.460
分娩方式[例（%）] ? ? χ2= 0.088 0.767
? 顺产 31（67.39） 29（64.44） ? ?
? 剖宫产 15（32.61） 16（35.56） ? ?
基线水平 ? ? ? ?
? HBsAg（log10IU/ml）a 4.47（4.30～4.65） 4.45（4.21～4.53） Z = 0.634 0.526
? HBeAg（S/CO）a 1 406.84（1 154.18～1 541.37） 1 389.92（1 209.01～1 539.06） Z=－0.056 0.955
? HBV DNA（log10IU/ml）a 8.09（7.55～8.23） 7.89（7.57～8.23） Z= 0.544 0.586
孕期ALT水平升高[例（%）] 0（0.00） 12（26.67） χ2= 13.846 <0.001b
停药时水平 ? ? ? ?
? HBsAg（log10IU/ml）a 4.46（4.27～4.62） 4.45（3.84～4.54） Z= 0.661 0.509
? HBeAg（S/CO）a 1 314（1 112.74～1 506.59） 1 305.18（1 020.89～1 112.74） Z=－0.524 0.605
? HBV DNA（log10IU/ml）a 3.91（3.37～4.45） 4.21（3.41～4.80） Z= 1.123 0.261
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